Operative management of midshaft clavicle fractures demonstrates better long-term outcomes: A systematic review and meta-analysis of randomised controlled trials

Introduction Midshaft clavicular fractures are common amongst young adults. Conservative or surgical treatment for definitive fracture management has been widely debate, both with their pros and cons. Previous meta-analyses compared the clinical outcomes between conservative and surgical treatment options of midshaft clavicular fractures but failed to elucidate any difference in functional improvement. We postulate that functional improvement after fracture union plateaus and the clinical outcome after treatment varies at different time points. This meta-analysis will focus on the synthesis comparison of outcomes at early, short-term results (3 months), intermediate-term (6 to 12 months) and long-term (>24 months) clinical outcomes. Methods A systematic search was done on databases (Pubmed, Embase, Medline, Cochrane) in June 2021. Search keywords were: midshaft clavicular fractures and clinical trials. Clinical trials fulfilling the inclusion criteria were selected for comparison and the clinical outcomes of midshaft clavicular fractures using surgical and non-surgical interventions in terms of improvement in the Disabilities of the Arm, Shoulder and Hand (DASH) score, Constant-Murley Score (CMS), time to union and risk ratio of treatment related complications were analysed in correlation with post-treatment timeframe. Results Of the 3094 patients of mean age 36.7 years in the 31 selected studies, surgical intervention was associated with improved DASH score (standard-mean difference SMD -0.22, 95% CI -0.36 to -0.07, p = 0.003; mean difference MD -1.72, 95% CI -2.93 to -0.51, p = 0.005), CMS (SMD 0.44, 95% CI 0.17–0.72, p = 0.001; MD 3.64, 95% CI 1.09 to 6.19, p = 0.005), time to union (non-adjusted SMD -2.83, 95% CI -4.59 to -1.07, p = 0.002; adjusted SMD -0.69, 95% CI -0.97 to -0.41, p<0.001) and risk ratio of bone-related complications including bone non-union, malunion and implant failure (0.21, 95% CI 0.1 to 0.42; p<0.001). Subgroup analysis based on time period after treatment showed that surgical intervention was far superior in terms of improved DASH score at the intermediate-term results (6–12 months later, SMD -0.16, 95% CI -0.30 to -0.02, p = 0.02; and long term results (>24 months SMD -4.24, 95% CI -7.03 to -1.45, p = 0.003) and CMS (>24 months, SMD 1.03, 95% CI 0.39 to 1.68, p = 0.002; MD 5.77, 95% CI 1.63 to 9.91, p = 0.006). Surgical outcome is independent of fixation with plates or intra-medullary nails. Conclusion Surgical intervention was associated with better clinical outcomes compared with non-surgical approach for midshaft clavicular fractures in terms of improvement in functional scores DASH, CMS, time to union and fracture related complications, although not to the minimal clinically significant difference. Benefits in the long-term functional improvements are more pronounced.


Introduction
Midshaft clavicular fracture occupies 2.6-4% of all adult fractures [1,2]. It is a common injury among young adults with over one-third of all clavicular fractures occurring in adolescent male, and one-fifth in adolescent female [3]. The middle third of the clavicle is especially vulnerable to traumatic injury since it is the thinnest part of the clavicle without reinforcement protection by muscle and ligamentous attachments. Midshaft clavicular fractures can be classified by the Neer Classification or AO classification for risk stratification and management [4,5]. Essentially, these classifications broadly classify them into non-displaced fractures (AO/ OTA classification type A) which can be managed conservatively, while management for displaced fractures (AO/OTA classification type B) remains controversial. Absolute surgical indications often quoted include: 1) open fractures; 2) complete displacement of fracture ends with fragments greater than the width of the clavicular bone; 3) clavicle shortening more than 2cm or with an angulation of more than 30 degrees [6]. Relative surgical indications are: 1) significantly displaced fractures with shortening; 2) bone fragment pressure endangering soft tissue recovery; 3) lateral third clavicular fracture; 4) floating shoulder; 5) recurrent fractures; 6) non-union or malunion related complications.
Conservative treatment, such as the use of an arm sling immobilization followed by gentle range of motion exercises has been associated with significant non-union rates (range: 11-30%), poor cosmesis and decreased shoulder and strength and endurance [7][8][9][10]. However, the surgical decision is individualized based on the shoulder functional demand of patients since surgical management has its own disadvantages such as longer time for bone union, complications such as infection, neurovascular injury and the need for secondary procedures including implant removal [11,12]. Clavicle implants have notoriously caused hardware impingement necessitating removal surgery in a high proportion of patients. Previous evidence does not support one management over the other. Early meta-analyses have summarised clinical trials comparing surgical interventions and conservative treatment but they show no functional differences between both interventions in short term; however, we postulate that surgical intervention leads to faster functional recovery compared to conservative means and better long-term prognosis [13][14][15]. Much of the patients attain fracture union and plateau in functional improvement with fair recovery in the long-term. Moreover, more detail on fracture fixation methods, approach and implants used may grossly affect the final outcome. This systematic review and meta-analysis aims at an updated comparison of the clinical outcomes between conservative treatment and surgical treatment of midshaft clavicular fracture at different time points (early, intermediate and late), and the subgroup analysis of management modalities within the surgical arm with the inclusion of most recent randomized control trials.

Methods
A systematic search was performed on databases (Pubmed, Embase, Medline, Cochrane) in June 2021. Search keywords were: midshaft clavicular fracture and clinical trials. Clinical studies fulfilling the inclusion criteria were selected to evaluate the treatment efficacy of conservative treatment and surgical treatment in terms of change in functional scores; the Constant-Murley score (CMS), Disability Assessment of Shoulder and Hand (DASH) scores and visual analogous score of pain, time taken for radiological union and risk ratio of complication rates. The inclusion criteria for patients were: 1) closed midshaft clavicular fractures; 2) aged 18 or above; 3) with informed consent and be able to comply with follow-up period; 4) medically fit for surgery and anaesthesia. Exclusion criteria were: 1) fracture at proximal or distal third of the clavicle; 2) polytrauma or presentation delayed beyond 24 hours post-injury; 3) pathological fracture; 4) open fractures; 5) associated neurovascular injuries; 6) medical contraindications to surgery or high risk of anaesthesia.
Conservative treatment includes sling immobilization, figure-of-eight bandages, analgesics and rehabilitation exercises, while surgical management options include closed reduction with intramedullary fixation or open reduction internal fixation (ORIF) often utilizing different fixation methods. These include anatomical and non-anatomical locking clavicular plate fixation via superior or anterosuperior plating, dynamic compression plating with non-locking screws, titanium elastic intramedullary nailing and minimally invasive plate osteosynthesis. Subgroup analysis and qualitative systemic review was performed comparing different fixation methods.

Data analysis
The primary aim of the review is to evaluate the efficacy of conservative treatment and surgical treatment for midshaft clavicular fractures. The primary outcome is the improvement functional scores (DASH and CMS) over time. DASH score is a function assessment to quantify the impact of the impairment on the level of arm, shoulder and hand-with a lower score signalling better functional outcome [16]. CMS is a 100-point scale that defines the level of pain and the ability to carry out normal daily activities of the patient with a higher score suggesting better functional return [17]. Previous studies have shown that the minimal clinically important difference for DASH and CMS were 10.83 points and 10.4 points, respectively [18,19]. Secondary outcomes include time to fracture union confirmed by radiological investigations and risk ratios of complication rates including malunion, non-union, chronic neuropathy by the end of the study follow-up. Early outcome after treatment is defined as 3 months, intermediate outcome as between 6 and 12 months and late outcome is classified as 24 months after treatment.
The titles, abstracts and full articles were independently screened by two authors (ZPY and WSY). Following the PRISMA guidelines in PRISMA flow diagram, the study profile is shown in Fig 1. Duplicate articles were removed from analysis and articles were excluded if they were reviews, conference abstracts, research protocols or articles without primary therapeutic data.
Data extraction was performed with focus on study design, population demographics and therapeutic outcomes. Bias assessment was performed by Cochrane collaboration tool for randomised controlled trial (RCT). Bias or quality issues were minimized by cross-checking and inter-rater reliability test between authors, using IBM SPSS Statistics for Windows, version 28 (IBM Corp., Armonk, N.Y., USA). An inter-rater reliability test Cronbach's Alpha of more than 0.7 as the acceptable inter-rater agreement [20]. Intraclass correlation coefficient was calculated with two-way mixed model of absolute agreement with a 95% confidence interval.
Review manager, version 5.3 and SPSS (IBM Corp., Armonk, N.Y., USA) were used in data analysis. Dichotomous data were pooled in random-effect model as a risk ratio with 95% confidence interval; while continuous data were pooled in random-effect model as a weighted average using generic inverse-variance method with 95% confidence interval. Heterogeneity was assessed with chi-square (χ 2 ) test, with p-value smaller than 0.1 as statistically significant. Its' extent was measured with I2-test. Egger's test for funnel plot asymmetry was performed for assessment of publication bias for outcome measures with at least 10 studies.

Results
As of June 2021, 4125 articles were retrieved from electronic databases (Pubmed, Embase, Scopus, Medline). After exclusion of duplicates and screening of titles and abstracts-articles were identified for full text review. A total of 49 articles were selected for eligibility assessment. 18 of them were excluded due to: (N = 10), protocol (N = 5) or non-English articles (N = 3). Eventually, 31 articles were selected for qualitative analysis. Amidst, 24 of them were included for meta-analysis review. Table 1 shows the summary of the pooled studies. Inter-rater variability is calculated with Cronbach's alpha 0.826, and intraclass correlation coefficient is 0.815 (95% CI 0.681-0.898).
The standard-mean difference of CMS at early, intermediate, and late outcomes were -0.12 (95% CI -0.13 to 0.37; p = 0.35), 0.18 (95% CI -0.09 to 0.44; p = 0.19) and 1.03 (95% CI 0.39 to 1.68; p = 0.002), respectively. The overall standard-mean difference in CMS is 0.44 (95% CI 0.17-0.72; p = 0.001) as shown in Fig 3. The mean differences of DASH score and CMS between surgical and non-surgical management is shown in Figs 4  Pooled data analysis for secondary outcomes in time to bony union and risk ratio for bone related complications are shown in Figs 6 and 7. A statistically significant reduction in time to achieve bony union was seen in the surgical intervention group with a standard-mean difference of -2.83 (95% CI -4.59 to -1.07; p = 0.002). The risk of bone-related major complications, including bone non-union, malunion and implant failure was lower in the surgical compared to the non-surgical group with a risk ratio of 0.21 (95% CI 0.1 to 0.42; p<0.001).

Surgical plate fixation versus intramedullary nailing
Subgroup analysis within the surgical intervention group on the type of fixation and approach used was also done (See S1 File). Surgical outcomes by fixation of plate compared to intramedullary nailing were compared. Functional outcomes as seen in S1 and S2 of S1 File, showed no difference in DASH score, standard-mean difference is 0.01 (95% CI -0.31 to 0.33; p = 0.94) Table 1. Summary of the selected studies which fulfilled the inclusion criteria: 1) closed midshaft clavicular fractures; 2) aged 18 or above; 3) with informed consent and be able to comply with follow-up period; 4) medically fit for surgery and anaesthesia. Exclusion criteria were: 1) fracture at proximal or distal third of the clavicle; 2) polytrauma or presentation delayed beyond 24 hours post-injury; 3) pathological fracture; 4) open fractures; 5) associated neurovascular injuries; 6) medical contraindications to surgery or high risk of anaesthesia. • Length of incision, operation time, blood loss and duration of hospital stay were significantly less for the EIN group. • American Shoulder and Elbow Surgeons (ASES) and Constant Shoulder scores were significantly higher (p<0.05) in the plating group than the EIN group for the first 2 months but there was no significant difference found between the two groups regarding functional and radiological outcome at the 2-year follow-up. • Significantly higher rates of refracture after implant removal (p = 0.045) in the plating group was observed. • Infection and revision surgery rates were also higher in the plate group, but this difference was insignificant (p>0.05).

Minimally invasive surgery versus conventional plate fixation
Different methods of plating has been described in clinical trials including the comparison between minimally invasive surgery (MIS) and conventional plate fixation. Jiang and Qu

Discussion
This systematic review and meta-analysis aimed to evaluate the difference in treatment choice for midshaft clavicular fractures with regards to early, intermediate, and late outcomes. Previous meta-analysis of 15 randomised controlled trials in 2015 showed that surgical and nonsurgical management had similar functional outcomes and complication rates after 1 year follow-up [13]. Another meta-analysis in 2019, also with 1-year follow-up still showed no difference in functional outcomes, but low rate of revision surgery and complications with surgical intervention [14]. Another recent meta-analysis with 14 RCT including 1546 patients showed an improvement of functional scores (DASH and CMS) and lower complication rates [15]. However, this meta-analysis defined short-term as 6 weeks with lacking data for CMS functional scores [15]. Moreover, time to bone union may range from 6 weeks to 13 weeks and short-term outcomes before bony union may be inaccurately assessed as functional rehabilitation and return may not yet be attainable [7,11,50]. Long-term data was broadly grouped and defined as >9 months in this study. To date, no meta-analysis has investigated into the difference between surgical and non-surgical interventions specifically for more than 2 years. This is the first meta-analysis to compare the difference in clinical outcomes of surgical interventions and non-surgical treatment with stratification into early (�3 months), intermediate (6-12 months) and late (�24 months) time-points to provide a holistic picture for treatment outcomes in the long term. This meta-analysis of 31 RCT involving 3094 patients showed that surgical fixation is a better treatment choice for midshaft clavicular fractures, compared with non-operative treatment. Better outcomes in terms of standard-mean difference of DASH score, CMS, time to union and risk ratio for associated complications were observed in surgical fixation group. Surgical intervention provides better mechanical stability, and we postulate a more rapid recovery of shoulder function-related scores. The overall and long term (�24 months) DASH scores in operative group were significantly better than the non-operative group; with a long term improvement by 4.24 points and a standard-mean difference suggestive of a large effect size. This is similarly true in the overall CMS and late CMS outcomes with a significant improvement by a difference of 5.77 score after 2 years. Surgical intervention also favours earlier restoration of shoulder function scores (both DASH and CMS) in the early and intermediate outcomes, but without statistical significance, contrary to what we postulated. Surgical intervention is associated with a shorter time to bone union (SMD -0.69, 95% CI -0.97 to -0.41, p<0.001) and lower risk of bone-related complications (risk ratio 0.21, 95% CI 0.1-0.42; p<0.001).
However, the difference and improvement in the DASH and CMS functional scores albeit significant did not reach the minimal clinically significant difference (MCID). Axelrod et al. and Franchignoni et al. showed that the established threshold for MCID of DASH score is between 8 and 10 points [19,51]; and the MCID of Constant score to be at a score 10.4 [18]. However, the mean difference in DASH and CMS between intermediate and late time-points continued to improve with the difference in mean CMS score doubling; suggesting that the clinical benefits of surgery may be more obvious in the long-term. The discussion of potential long-term functional benefits with patients in day-to-day clinical practice can help them decide on their choice of treatment.
Given that more evidence suggests surgical intervention has better outcomes than nonoperative treatment-ways to optimize surgical approach for midshaft clavicular fractures needs to be investigated. In this study we also compared the surgical outcomes between intramedullary nail (IM nail) and plate fixation in terms of functional DASH scores and CMS, time to union and fracture related complications rate. However, no statistically significant difference was found. Both implants are safe options for surgical fixation but subject to variability in fracture pattern and surgeon preference [38,42]. IM nail has the theoretical advantage of preserving the periosteal blood supply, but carries the higher risk of pin migration and nonunion with less rigid fixation [36]. Fuglesang et al. recommended the use of plate fixation in patients with comminuted fractures due to a quicker recovery and IM nail for non-comminuted fractures since it is associated with shorter operative time, lower infection and implant failure rate, better cosmetic outcomes and earlier return to work [40,41]. IM nailing is inherently difficult to be performed in comminuted fractures and may not be appropriate for such fracture patterns. In addition, Hulsman et al. found that implant removal rate in IM nailing  There were several limitations to this study. Despite all included studies being RCTs, there was significant heterogeneity between studies including patient population and surgical techniques. For example, different type of implants used including: anatomical and non-anatomical locking plates, dynamic compression plates and IM nails. Also differences in surgical approaches with superior or anterior plating. Further network meta-analyses are required to investigate the optimum surgical fixation method and approach on functional outcomes. Other commonly seen complications such as infections (superficial and deep), poor shoulder cosmesis and rate of implant removal for symptomatic hardware were not assessed in this study. Lastly, the sensitivity of DASH and CMS functional scores used in this study in detecting subtle clinically significant differences has also been raised into question. Differences in healthy young adults may not be detected for example, small power deficits with a shortened muscular lever arm with the loss of clavicle length in non-operative management [52, 53].

Conclusion
Surgical intervention for midshaft clavicle fractures is associated with better clinical outcomes compared with non-surgical management for midshaft clavicular fractures in terms of functional improvement in DASH and CMS, with benefit seen in long-term results albeit not to the MCID. Time to bone union and fracture related complications were also improved with surgical intervention. There was no significant difference in outcomes between surgical fixation with plating or intramedullary nailing. Further studies are needed to determine the optimal surgical fixation method and approach.